Efficacy and safety of methotrexate in alopecia areata

Lalu yogi prasetio imam

Alopecia areata (AA) is a chronic, multifactorial condition of the hair follicles and nails, of unknown etiology, with clear genetic and autoimmune components. It is a common complaint at the dermatologist’s office, accounting for 0.7 to 3.8% of visits. Depending on the number and distribution of lesions and the extent of involvement, it is classified clinically into the following patterns: unifocal, multifocal, ophiasis, totalis, universalis, sisaipho (or ophiasis inversus), reticular, and diffuse

• Regarding the natural history of the disease, hair regrowth occurs in 34% to 50% of patients within 1 year, whereas 15% to 25% will progress to AA totalis (loss of all scalp hair). There is a direct association between the severity of AA and the long-term prognosis. Available treatments may induce regrowth, but do not modify the disease course.

Potential autoimmune mechanisms involved in the pathogenesis of AA include sensitization of T lymphocytes, particularly CD8+ T cells, to follicular antigens. Activation of the lymphocytes that compose the perifollicular infiltrate characteristic of AA induces release of several Th1 cytokines – interleukin (IL)-1 alpha, IL-1 beta, and tumor necrosis factor (TNF) alpha– capable of inhibiting hair follicle growth and arresting hair synthesis, with early termination of anagen

• Several treatment options have been suggested for AA, but there is a paucity of randomized, doubleblind, placebo-controlled trials, and, as noted above, no therapy is able to modify the course of the disease.

• Methotrexate (MTX) is an immunosuppressant agent of the folic acid antagonist class that is used in the treatment of several dermatoses. Most dermatologists are used to its prescription and monitoring, particularly in the treatment of psoriasis. MTX was recently introduced as a therapeutic option for AA

Objectives

• To assess the efficacy and safety of MTX in AA, whether as monotherapy or in combination with other treatment modalities, such as systemic or intralesional corticosteroids; and to assess therapeutic response according to sex, age, pattern of AA, disease duration, cumulative MTX dose, and duration of therapy

METHODS

• This retrospective study evaluated 31 patients with AA seen at the outpatient hair disorders clinic of Hospital de Clínicas de Curitiba (state of Paraná, Brazil) and at private dermatology practices in Curitiba who were on current or prior MTX therapy. The sample comprised patients with extensive forms of AA (multifocal, universalis, totalis, and diffuse),refractory to previous treatment attempts, who were over 15 years of age.

• The following characteristics were considered as criteria for MTX prescription: absence of hepatic impairment (confirmed by laboratory testing), absence of active tuberculosis infection (confirmed by clinical examination or PPD and chest X-ray), absenceof pregnancy, and COCP (combined oral contraceptive) use. Furthermore, patients were informed of possible side effects and MTX was only prescribed after patient consent had been obtained.

• We evaluated the following parameters: disease duration, concomitant therapies (including systemic corticosteroid therapy), pattern of alopecia, weekly MTX dose, cumulative dose of MTX in mg (stratified into predetermined ranges: <500 mg; 501-1000 mg; 1001-1500 mg; 1501-2000 mg; 2001-2500 mg; and >2500 mg), hematologic and/or hepatic adverse events, treatment duration, and therapeutic response. Regrowth was stratified into five categories: 0-25%; 26-50%; 51-75%; 76-99%; and 100%.

• All patients underwent a comprehensive outpatient workup, which included a complete blood count and measurement of transaminase, creatinine, bilirubin, and gamma-glutamyl transpeptidase levels, at baseline, 1 month, and every 3 months thereafter during the follow-up period. In some patients, a chest X-ray, PPD skin testing, and a hepatitis serology panel were also performed before treatment. Patients who received a total cumulative dose of MTX >2 g underwent abdominal ultrasound and liver biopsy.

RESULTS

• The median patient age was 40 years (range, 15- 72 years), and the median disease duration was 4 years (range, 0.17-32 years). Of the patients assessed, 66.6% were female and 33.3% were male (Table 1). The most common pattern of AA was multifocal (48.39%), followed by universalis (35.48%), diffuse (9.67%), and totalis (6.45%).

• Most patients had received previous trials of• therapy, such as topical sensitizers (58%) and systemic• corticosteroids (51.6%), either unsuccessfully or with• disease recurrence after withdrawal of treatment.• The starting dose of MTX ranged from 10 to 25• mg (±15 mg), as did the median therapeutic dose (±20• mg). The cumulative dose to onset of response ranged• from 30 to 630 mg (±180 mg). The distribution of• cumulative doses in the sample was as follows: <500• mg, 25.8%; 501-1000 mg, 29%; 1001-1500 mg, 19.3%;• 1501-2000 mg, 12.9%; and >2000 mg, 12.9%.

• A therapeutic response with regrowth over• >50% of the scalp (Figures 1, 2, and 3), considered

cosmetically• acceptable, was observed in 67.7% (n=21) of• all patients, with 29% (n=9) achieving 76-99%• regrowth and 19.3% (n=6) achieving 100% regrowth.• The frequency of regrowth was significantly greater• among men (72.8%, p>0.05), patients aged 40 years or• older (73.3%, p>0.05), and those taking a cumulative• MTX dose of 1001-1500 mg (83.3%, p>0.05) (Table 2).

• Furthermore, superior responses were• observed in patients with a disease duration <5 years• (79% regrowth), with the overall regrowth rate dropping• to 50% in patients with disease duration >5• years. There was a significant inverse association• between disease duration and percent improvement• (p=0.02); the shorter the disease duration, the greater• the improvement. Regarding AA patterns, >50%• regrowth was observed in 93.3% (n=14) with multifocal,• 45.4% (n=5) with universalis, 50% (n=1) with totalis,• and 33.3% (n=1) with diffuse AA. The difference• between the two most prevalent forms, universalis• and multifocal, was significant (p=0.018) (Table 3).

• The treatments combined with MTX included• topical minoxidil, intralesional corticosteroids, and• systemic corticosteroids (prednisone). Only one• patient did not use any combination therapy. The• most common combination therapy added to MTX• was topical minoxidil + systemic corticosteroid (29%).

• Among the patients who used systemic corticosteroids• in combination with MTX (70%), 77.3%• experienced >50% regrowth. Most used steroids only during the

first months of treatment. Among those• who did not use systemic corticosteroids in combination• with MTX (30%), only 44.4% experienced >50%• regrowth. There was no significant association• between corticosteroid therapy and treatment• response. The duration of combination corticosteroid• therapy ranged from 1 to 12 months (±4 months), and• the dose, from 20 to 30 mg/day (±30 mg).

• All patients underwent complete blood count• and liver and kidney function tests at baseline. Nine• also underwent hepatitis serologies (all non-reagent)• and nine underwent PPD testing, of whom three were• strongly reactive, despite normal chest X-ray.• All patients received folic acid supplementation• (5 mg) at least one weekly, on the day after MTX. Folic• acid administration was increased to three weekly• doses in patients with MTX intolerance or gastric or• hematologic adverse effects.

• Regarding treatment tolerance, only three• patients (9.3%) reported gastrointestinal side effects• (nausea, epigastric pain, and diarrhea), which were• managed by scaling up folic acid supplementation• and dividing the MTX dose, with improvement of• symptoms in two patients; only one required treatment• discontinuation.• Hematologic adverse effects (mild to moderate• leukopenia, without clinical significance) were• observed in 9.7% (n=3) of patients, and improved after• folic acid supplementation was increased.

• Hepatic adverse effects (mild, transient increase• in transaminases) were observed in 6.5% (n=2) of• patients, one of whom had alcoholism. Abdominal• ultrasound and liver biopsy, performed in three• patients with a cumulative MTX dose of >2 g (9.6% of• patients), were within normal limits.

• The duration of follow-up ranged from 3 to 51• months (±13). Relapse occurred in 33.3% (n=7) of• patients with >50% regrowth (n=21) and in 40% (n=6)• of patients with >75% regrowth (n=15). One patient• developed relapse during treatment, three at the time• of treatment withdrawal (after dose reduction to <7.5• mg/week), and three after a mean 6.3 months after• MTX discontinuation. The pattern of alopecia at• relapse was multifocal (small plaques) in six patients• and AA totalis in one patient. Options for relapse• management included initiation of prednisone,• increase in MTX dosage, intralesional corticosteroids,• or topical dithranol.

DISCUSSION

• Several therapeutic options are available for the• treatment of extensive or refractory AA. These

include• intralesional, topical, or systemic corticosteroids;• minoxidil; dithranol; topical sensitizers (DNCB,• DPCP); and PUVA. However, none of these

modalities has proven curative or preventative action

• Methotrexate (4-amino-N-methylpteroylglutamic• acid, MTX) is a folic acid antagonist and a derivative• of aminopterin.12 Approved as an antineoplastic• agent in 1953 and for the treatment of psoriasis in• 1971,13 MTX acts as an immunosuppressant and is• used in the treatment of several skin conditions, such• as psoriasis, bullous dermatoses, collagen storage disorders,• vasculitides, neutrophilic dermatoses, and• atopic dermatitis.13 Recently, it has been used in the• treatment of AA, with satisfactory results

• In the circulation, 50% of MTX is proteinbound.• It exhibits particular affinity for hepatocytes,• myeloid precursors, red blood cells, and fibroblasts. It• is converted to its predominantly active

polyglutamate• metabolite, which persists for months and• allows weekly dosing.12,13 Excretion is mostly renal• and, to a lesser extent, biliary

• Although the mechanism of action of MTX is• not entirely understood, it is known to inhibit the• enzyme dihydrofolate reductase, which leads to a• decrease in intracellular reduced folate concentrations.• This decrease inhibits purine and pyrimidine• metabolism and, consequently, nucleic acid synthesis,• thus resulting in antineoplastic effects when administered• at high doses.11 MTX polyglutamates also inhibit• AICAR (5-aminoimidazole-4-carboxamide ribonucleotide• formyltransferase), an enzyme involved in• purine synthesis, which ultimately leads to a buildup• of adenosine, a mediator of many of the anti-inflammatory• effects of MTX. Adenosine is released into the• extracellular space and, among multiple anti-inflammatory• actions, inhibits white blood cell accumulation,• leads to a reduction in TNF-α and IFN-γ synthesis,• and inhibits a variety of monocyte, macrophage,• and T-cell activities.12,13 This action might explain the• effect of MTX in AA.

• In this study, MTX was used in severe forms of• AA (multifocal, universalis, totalis, and diffuse) to• good effect (>50% regrowth in 67.7% of cases), with• few adverse effects. These results are similar to those• reported in prior studies: Joly (2010) and Droitcourt• (2012) reported satisfactory regrowth in 64% and 70%• of patients respectively.10,11 A study conducted in

children• also found no serious side effects, with >50%• regrowth in five of 13 patients assessed.

• The factors associated with a higher incidence of• response (although not significantly so) were male sex,• age >40 years, systemic corticosteroid therapy, and a• cumulative MTX dose of 1001-1500 mg. Other factors,• such as multifocal AA and disease duration <5 years,• were significantly associated with response, and may• thus be defined as indicators of better prognosis. A• direct association between severity of AA and longterm• prognosis has been demonstrated previously

• The use of systemic corticosteroids in combination• with MTX in the early months of treatment may• mask therapeutic response. Nevertheless, it was

associated• with improved response, as in previous studies,• although the difference was not significant in the

present• sample.

• The main short-term adverse effects are hematologic,• particularly pancytopenia. Other adverse• effects include mucositis, oral and/or gastrointestinal• ulcers, rash, photosensitivity, acne, alopecia, anorexia,• diarrhea, nausea, and interstitial pneumonitis, particularly• in patients with hypoalbuminemia. Long-term• adverse effects are mostly hepatic, and may range• from elevated transaminases to steatosis and cirrhosis.• 12,13 Other long-term effects include pulmonary• fibrosis, malignancy (increased risk of lymphoma in• patients with psoriasis or rheumatoid arthritis), and• increased risk of occlusive vascular disease (due to• increased homocysteine levels).

• Based on the folate-depleting mechanism of• action (both therapeutic and toxic) of MTX, studies• have been conducted to assess the effect of folic acid• or folinic acid supplementation given after MTX• doses; all have demonstrated a reduction in adverse• effects without loss of efficacy.13,15 In the present

study,• folic acid was administered at a dose of 5 mg once to• three times weekly.

• The risk of hepatotoxicity is increased in the• presence of excess alcohol intake, concomitant• retinoid therapy, diabetes mellitus, or obesity.13,16 In

the• present study, two patients developed increased• transaminases: one with a history of alcoholism (a• known risk factor) and one on concomitant nonsteroidal• anti-inflammatory drug therapy, which may• increase plasma levels of MTX.

• Assessment of hepatic fibrosis may be performed• by means of invasive (biopsy) and non-invasive• (ultrasound, Fibroscan, and serum markers).25,26 In• the present study, three patients with a cumulative• dose >2 g underwent hepatic biopsy, which revealed• no changes.

• In our sample, the mean therapeutic dose of• MTX was approximately 20 mg and the dose required• for onset of regrowth was 180 mg, i.e., onset of• response took approximately 9 weeks (2.1 months).• Joly (2010) and Droitcourt (2012) reported similar• times to response onset: 2.5 and 3 months respectively.• 9,10 Most patients with >50% regrowth received• cumulative doses in the 1000-1500 mg range (87%),• which suggests that these dose levels must be• achieved before therapeutic response can be assessed.

• A previous study found an 80% relapse rate in• MTX-treated patients who experienced regrowth.9 In• our sample, relapse occurred in 33.3% (n=7) of• patients with >50% regrowth (n=21), and in 20% of• patients with >75% regrowth. One patient developed• relapse during treatment, three at the time of treatment• withdrawal (after dose reduction to <7.5• mg/week), and three a mean 6.3 months after MTX• discontinuation, which suggests that an MTX dose of• 7.5 mg/week is a good level to define the timing of• drug discontinuation or the minimum effective dose• for maintenance of remission.

CONCLUSION• MTX at a mean dose of 20 mg/week appears to• be a safe and promising option for the treatment of• severe forms of AA. A mean cumulative dose of 180• mg was required for onset of response, and total• cumulative doses of 1000-1500 mg were associated• with the best responses.• Limitations of this study include the heterogeneity• of the sample (patients recruited from a public• hospital and from private practices), as well as the• retrospective, non-comparative nature of the study.• Larger samples studied in a blind, randomized fashion• are required to establish MTX as first-line therapy• for AA. The use of biomarkers currently in development• for patient monitoring may encourage longterm• use of MTX without requiring patients to undergo• invasive testing.